A study of putative p25 modulated synaptic molecules - CYFIP1, CYFIP2 and CSPα - in Alzheimer's disease
Alzheimer’s Disease (AD) is a devastating neurodegenerative condition with synaptic impairment at the onset of disease. Previously, our group have shown that the p25 molecule is changed in the post mortem brain of mild stage AD patients. A mass spectrometric analysis of p25 transgenic mouse brain pr...
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ndltd-bl.uk-oai-ethos.bl.uk-6771302017-07-25T03:29:49ZA study of putative p25 modulated synaptic molecules - CYFIP1, CYFIP2 and CSPα - in Alzheimer's diseaseTiwari, Sachin SureshHortobagyi, Tibor ; Hirth, Frank ; Giese, Karl Peter2015Alzheimer’s Disease (AD) is a devastating neurodegenerative condition with synaptic impairment at the onset of disease. Previously, our group have shown that the p25 molecule is changed in the post mortem brain of mild stage AD patients. A mass spectrometric analysis of p25 transgenic mouse brain provided us with a set of potential p25 downstream molecules. Three of these candidate molecules which had synaptic/dendritic localization – CYFIP2, CYFIP1 and CSPα were selected to be studied in the post-mortem brain of Alzheimer’s patients. CYFIP2 is a dendritically localised molecule with biological role in local translation modulation and cytoskeleton remodelling. Our case –control studies revealed that CYFIP2 is downregulated in severe stages of disease in hippocampus. We showed a similar CYFIP2 downregulation in Tg2576 mouse model of AD. We performed functional studies of this molecule, using CYFIP2 heterozygous knockout mice. We found that these mutants suffer from memory loss after Pavlovian conditioning. CYFIP1 has similar cellular function as CYFIP2. Our studies showed that CYFIP1 is upregulated in AD hippocampus. However, this upregulation is unlikely to be compensation for CYFIP2 downregulation, as it was not observed in superior temporal gyrus. CSPα, a synaptic vesicle protein that has been implicated in neurodegeneration in Kufs disease, was found to be downregulated in AD hippocampus, but, surprisingly, upregulated in cerebellum. This suggests that CSPα may protect neurons from degeneration. In agreement, we found that CSPα upregulation in htau mutant mice correlates with absence of neuronal loss. Taken together, analysis of candidate p25-regulated synaptic proteins have provided novel insights into mechanisms underlying synaptic degeneration and memory impairment in AD.616.8King's College London (University of London)http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.677130http://kclpure.kcl.ac.uk/portal/en/theses/a-study-of-putative-p25-modulated-synaptic-molecules--cyfip1-cyfip2-and-csp--in-alzheimers-disease(2a989df1-ced0-4707-bfc7-4df22ca9fff4).htmlElectronic Thesis or Dissertation |
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616.8 Tiwari, Sachin Suresh A study of putative p25 modulated synaptic molecules - CYFIP1, CYFIP2 and CSPα - in Alzheimer's disease |
description |
Alzheimer’s Disease (AD) is a devastating neurodegenerative condition with synaptic impairment at the onset of disease. Previously, our group have shown that the p25 molecule is changed in the post mortem brain of mild stage AD patients. A mass spectrometric analysis of p25 transgenic mouse brain provided us with a set of potential p25 downstream molecules. Three of these candidate molecules which had synaptic/dendritic localization – CYFIP2, CYFIP1 and CSPα were selected to be studied in the post-mortem brain of Alzheimer’s patients. CYFIP2 is a dendritically localised molecule with biological role in local translation modulation and cytoskeleton remodelling. Our case –control studies revealed that CYFIP2 is downregulated in severe stages of disease in hippocampus. We showed a similar CYFIP2 downregulation in Tg2576 mouse model of AD. We performed functional studies of this molecule, using CYFIP2 heterozygous knockout mice. We found that these mutants suffer from memory loss after Pavlovian conditioning. CYFIP1 has similar cellular function as CYFIP2. Our studies showed that CYFIP1 is upregulated in AD hippocampus. However, this upregulation is unlikely to be compensation for CYFIP2 downregulation, as it was not observed in superior temporal gyrus. CSPα, a synaptic vesicle protein that has been implicated in neurodegeneration in Kufs disease, was found to be downregulated in AD hippocampus, but, surprisingly, upregulated in cerebellum. This suggests that CSPα may protect neurons from degeneration. In agreement, we found that CSPα upregulation in htau mutant mice correlates with absence of neuronal loss. Taken together, analysis of candidate p25-regulated synaptic proteins have provided novel insights into mechanisms underlying synaptic degeneration and memory impairment in AD. |
author2 |
Hortobagyi, Tibor ; Hirth, Frank ; Giese, Karl Peter |
author_facet |
Hortobagyi, Tibor ; Hirth, Frank ; Giese, Karl Peter Tiwari, Sachin Suresh |
author |
Tiwari, Sachin Suresh |
author_sort |
Tiwari, Sachin Suresh |
title |
A study of putative p25 modulated synaptic molecules - CYFIP1, CYFIP2 and CSPα - in Alzheimer's disease |
title_short |
A study of putative p25 modulated synaptic molecules - CYFIP1, CYFIP2 and CSPα - in Alzheimer's disease |
title_full |
A study of putative p25 modulated synaptic molecules - CYFIP1, CYFIP2 and CSPα - in Alzheimer's disease |
title_fullStr |
A study of putative p25 modulated synaptic molecules - CYFIP1, CYFIP2 and CSPα - in Alzheimer's disease |
title_full_unstemmed |
A study of putative p25 modulated synaptic molecules - CYFIP1, CYFIP2 and CSPα - in Alzheimer's disease |
title_sort |
study of putative p25 modulated synaptic molecules - cyfip1, cyfip2 and cspα - in alzheimer's disease |
publisher |
King's College London (University of London) |
publishDate |
2015 |
url |
http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.677130 |
work_keys_str_mv |
AT tiwarisachinsuresh astudyofputativep25modulatedsynapticmoleculescyfip1cyfip2andcspainalzheimersdisease AT tiwarisachinsuresh studyofputativep25modulatedsynapticmoleculescyfip1cyfip2andcspainalzheimersdisease |
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1718505055441649664 |